Divergent Ca(2+)/calmodulin feedback regulation of Ca(V)1 and Ca(V)2 voltage-gated calcium channels evolved in the common ancestor of Placozoa and Bilateria

Ca(V)1 and Ca(V)2 voltage-gated calcium channels evolved from an ancestral Ca(V)1/2 channel via gene duplication somewhere near the stem animal lineage. The divergence of these channel types led to distinguishing functional properties that are conserved among vertebrates and bilaterian invertebrates and contribute to their unique cellular roles. One key difference pertains to their regulation by calmodulin (CaM), wherein bilaterian Ca(V)1 channels are uniquely subject to pronounced, buffer-resistant Ca(2+)/CaM-dependent inactivation, permitting negative feedback regulation of calcium influx in response to local cytoplasmic Ca(2+) rises. Early diverging, nonbilaterian invertebrates also possess Ca(V)1 and Ca(V)2 channels, but it is unclear whether they share these conserved functional features. The most divergent animals to possess both Ca(V)1 and Ca(V)2 channels are placozoans such as Trichoplax adhaerens, which separated from other animals over 600 million years ago shortly after their emergence. Hence, placozoans can provide important insights into the early evolution of Ca(V)1 and Ca(V)2 channels. Here, we build upon previous characterization of Trichoplax Ca(V) channels by determining the cellular expression and ion-conducting properties of the Ca(V)1 channel orthologue, TCa(V)1. We show that TCa(V)1 is expressed in neuroendocrine-like gland cells and contractile dorsal epithelial cells. In vitro, this channel conducts dihydropyridine-insensitive, high-voltage–activated Ca(2+) currents with kinetics resembling those of rat Ca(V)1.2 but with left-shifted voltage sensitivity for activation and inactivation. Interestingly, TCa(V)1, but not TCa(V)2, exhibits buffer-resistant Ca(2+)/CaM-dependent inactivation, indicating that this functional divergence evolved prior to the emergence of bilaterian animals and may have contributed to their unique adaptation for cytoplasmic Ca(2+) signaling within various cellular contexts.